Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Cardiovascular risk factors, radiation therapy, and myocardial infarction among lymphoma survivors.

BACKGROUND: Mediastinal radiation is associated with increased risk of myocardial infarction (MI) among non-Hodgkin lymphoma (NHL) survivors. OBJECTIVE: To evaluate how preexisting cardiovascular risk factors (CVRFs) modify the association of mediastinal radiation and MI among a national population of NHL survivors with a range of CVRFs. MATERIAL AND METHODS: Using Danish registries, we identified adults diagnosed with lymphoma 2000-2010. We assessed MI from one year after diagnosis through 2016. We ascertained CVRFs (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at lymphoma diagnosis. We used multivariable Cox regression to test the interaction between preexisting CVRFs and receipt of mediastinal radiation on subsequent MI. RESULTS: Among 3151 NHL survivors (median age 63, median follow-up 6.5 years), 96 were diagnosed with MI. Before lymphoma, 32% of survivors had ≥1 CVRF. 8.5% of survivors received mediastinal radiation. In multivariable analysis, we found that mediastinal radiation (HR = 1.96; 95% CI = 1.09-3.52), and presence of ≥1 CVRF (HR = 2.71; 95% CI = 1.77-4.15) were associated with an increased risk of MI. Although there was no interaction on the relative scale (p = 0.14), we saw a clinically relevant absolute increase in risk for patients with CVRF from 10-year of MI of 10.5% without radiation to 29.5% for those undergoing radiation. CONCLUSION: Patients with CVRFs have an importantly higher risk of subsequent MI if they have mediastinal radiation. Routine evaluation of CVRFs and optimal treatment of preexisting cardiovascular disease should continue after receiving cancer therapy. In patients with CVRFs, mediastinal radiation should only be given if oncologic benefit clearly outweighs cardiovascular harm.

Risk stratification of cardiac metastases using late gadolinium enhancement cardiovascular magnetic resonance: prognostic impact of hypo-enhancement evidenced tumor avascularity.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is widely used to identify cardiac neoplasms, for which diagnosis is predicated on enhancement stemming from lesion vascularity: Impact of contrast-enhancement pattern on clinical outcomes is unknown. The objective of this study was to determine whether cardiac metastasis (CMET) enhancement pattern on LGE-CMR impacts prognosis, with focus on heterogeneous lesion enhancement as a marker of tumor avascularity. METHODS: Advanced (stage IV) systemic cancer patients with and without CMET matched (1:1) by cancer etiology underwent a standardized CMR protocol. CMET was identified via established LGE-CMR criteria based on lesion enhancement; enhancement pattern was further classified as heterogeneous (enhancing and non-enhancing components) or diffuse and assessed via quantitative (contrast-to-noise ratio (CNR); signal-to-noise ratio (SNR)) analyses. Embolic events and mortality were tested in relation to lesion location and contrast-enhancement pattern. RESULTS: 224 patients were studied, including 112 patients with CMET and unaffected (CMET -) controls matched for systemic cancer etiology/stage. CMET enhancement pattern varied (53% heterogeneous, 47% diffuse). Quantitative analyses were consistent with lesion classification; CNR was higher and SNR lower in heterogeneously enhancing CMET (p < 0.001)-paralleled by larger size based on linear dimensions (p < 0.05). Contrast-enhancement pattern did not vary based on lesion location (p = NS). Embolic events were similar between patients with diffuse and heterogeneous lesions (p = NS) but varied by location: Patients with right-sided lesions had threefold more pulmonary emboli (20% vs. 6%, p = 0.02); those with left-sided lesions had lower rates equivalent to controls (4% vs. 5%, p = 1.00). Mortality was higher among patients with CMET (hazard ratio [HR] = 1.64 [CI 1.17-2.29], p = 0.004) compared to controls, but varied by contrast-enhancement pattern: Diffusely enhancing CMET had equivalent mortality to controls (p = 0.21) whereas prognosis was worse with heterogeneous CMET (p = 0.005) and more strongly predicted by heterogeneous enhancement (HR = 1.97 [CI 1.23-3.15], p = 0.005) than lesion size (HR = 1.11 per 10 cm [CI 0.53-2.33], p = 0.79). CONCLUSIONS: Contrast-enhancement pattern and location of CMET on CMR impacts prognosis. Embolic events vary by CMET location, with likelihood of PE greatest with right-sided lesions. Heterogeneous enhancement-a marker of tumor avascularity on LGE-CMR-is a novel marker of increased mortality risk.

Cardio-oncology Training in the COVID-19 Era.

OPINION STATEMENT: Cardio-oncology is a field dedicated to the prevention, diagnosis, and management of cardiovascular disease in cancer patients before, during, and after cancer therapy. It is an emerging field with limited opportunities for structured education and training. In the year 2021, we cannot define the requirements of cardio-oncology training without acknowledging the impact of the global coronavirus disease 19 (COVID-19) pandemic. While this pandemic poses significant health risks to patients with cancer and cardiovascular disease as well as the providers who care for them, it also allows novel opportunities for the nascent field of cardio-oncology to readily adapt. In this article, we detail how the COVID-19 pandemic has impacted all aspects of cardio-oncology training, how programs and trainees can adapt to these challenges, and how lessons learned from the COVID-19 era can continue to positively impact cardio-oncology training for the foreseeable future.

Myocarditis Surveillance in Patients with Advanced Melanoma on Combination Immune Checkpoint Inhibitor Therapy: The Memorial Sloan Kettering Cancer Center Experience.

This letter to the editor describes myocarditis screening among patients undergoing combination immune checkpoint inhibitor therapy, in light of the consensus document from the Checkpoint Inhibitor Safety Working Group.

Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction.

PURPOSE: Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline. METHODS: Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death. RESULTS: Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29). CONCLUSION: Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.

Development and Validation of a Clinical Score for Cardiovascular Risk Stratification of Long-Term Childhood Cancer Survivors.

BACKGROUND: Long-term childhood cancer survivors (CCS) are at increased risk of adverse cardiovascular events; however, there is a paucity of risk-stratification tools to identify those at higher-than-normal risk. SUBJECTS, MATERIALS, AND METHODS: This was a population-based study using data from the Surveillance, Epidemiology, and End Results Program (1973-2013). Long-term CCS (age at diagnosis ≤19 years, survival ≥5 years) were followed up over a median time period of 12.3 (5-40.9) years. Independent predictors of cardiovascular mortality (CVM) were combined into a risk score, which was developed in a derivation set (n = 22,374), and validated in separate patient registries (n = 6,437). RESULTS: In the derivation registries, older age at diagnosis (≥10 years vs. reference group of 1-5 years), male sex, non-white race, a history of lymphoma, and a history of radiation were independently associated with an increased risk of CVM among long-term CCS (p < .05). A risk score derived from this model (Childhood and Adolescence Cancer Survivor CardioVascular score [CHACS-CV], range: 0-8) showed good discrimination for CVM (Harrell's C-index [95% confidence interval (CI)]: 0.73 [0.68-0.78], p < .001) and identified a high-risk group (CHACS-CV ≥6), with cumulative CVM incidence over 30 years of 6.0% (95% CI: 4.3%-8.1%) versus 2.6% (95% CI: 1.8%-3.7%), and 0.7% (95% CI: 0.5%-1.0%) in the mid- (CHACS-CV = 4-5) and low-risk groups (CHACS-CV ≤3), respectively (plog-rank < .001). In the validation set, the respective cumulative incidence rates were 4.7%, 3.1%, and 0.8% (plog-rank < .001). CONCLUSION: We propose a simple risk score that can be applied in everyday clinical practice to identify long-term CCS at increased cardiovascular risk, who may benefit from early cardiovascular screening, and risk-reduction strategies. IMPLICATIONS FOR PRACTICE: Childhood cancer survivors (CCS) are known to be at increased cardiovascular risk. Currently available prognostic tools focus on treatment-related adverse events and late development of congestive heart failure, but there is no prognostic model to date to estimate the risk of cardiovascular mortality among long-term CCS. A simple clinical tool is proposed for cardiovascular risk stratification of long-term CCS based on easily obtainable information from their medical history. This scoring system may be used as a first-line screening tool to assist health care providers in identifying those who may benefit from closer follow-up and enable timely deployment of preventive strategies.

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The "Checkpoint Inhibitor Safety Working Group," a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.

Aspirin Is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction.

BACKGROUND: Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI). MATERIALS AND METHODS: Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005-2014 were reviewed. sTP was defined as a platelet count <50,000 cells per µL within 7 days of AMI. RESULTS: Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p = .0001) and thienopyridine treatment (27% vs. 3%; p = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use. CONCLUSION: Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding. The Oncologist 2017;22:213-221Implications for Practice: In patients with hematologic malignancies and acute myocardial infarction with severe thrombocytopenia (platelet count < 50,000 cells/µL), guideline-recommended medical therapy is often withheld because of the fear of major bleeding. In this study, aspirin therapy was associated with improved survival without an increase in major bleeding in this high-risk patient cohort.

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer.

BACKGROUND: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. METHODS: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. RESULTS: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy. CONCLUSION: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. IMPLICATIONS FOR PRACTICE: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer.

PURPOSE: Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting. METHODS: A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to <55% or >16% from baseline). RESULTS: A total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy. CONCLUSIONS: The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.

Prognostic utility of differential tissue characterization of cardiac neoplasm and thrombus via late gadolinium enhancement cardiovascular magnetic resonance among patients with advanced systemic cancer.

BACKGROUND: Late gadolinium enhancement (LGE-) cardiovascular magnetic resonance (CMR) is well-validated for cardiac mass (CMASS) tissue characterization to differentiate neoplasm (CNEO) from thrombus (CTHR): Prognostic implications of CMASS subtypes among systemic cancer patients are unknown. METHODS: CMASS + patients and controls (CMASS -) matched for cancer diagnosis and stage underwent a standardized CMR protocol, including LGE-CMR (IR-GRE) for tissue characterization and balanced steady state free precession cine-CMR (SSFP) for cardiac structure/function. CMASS subtypes (CNEO, CTHR) were respectively defined by presence or absence of enhancement on LGE-CMR; lesions were quantified for tissue properties (contrast-to-noise ratio (CNR); signal-to-noise ratio (SNR) and size. Clinical follow-up was performed to evaluate prognosis in relation to CMASS etiology. RESULTS: The study population comprised 126 patients with systemic neoplasms referred for CMR, of whom 50% (n = 63) had CMASS + (CNEO = 32%, CTHR = 18%). Cancer etiology differed between CNEO (sarcoma = 20%, lung = 18%) and CTHR (lymphoma = 30%, GI = 26%); cardiac function (left ventricular ejection fraction: 63 ± 9 vs. 62 ± 10%; p = 0.51∣ right ventricular ejection fraction: 53 ± 9 vs. 54 ± 8%; p = 0.47) and geometric indices were similar (all p = NS). LGE-CMR tissue properties assessed by CNR (13.1 ± 13.0 vs. 1.6 ± 1.0; p < 0.001) and SNR (29.7 ± 20.4 vs. 15.0 ± 11.4, p = 0.003) were higher for CNEO, consistent with visually-assigned diagnostic categories. CTHR were more likely to localize to the right atrium (78% vs. 25%, p < 0.001); nearly all (17/18) were associated with central catheters. Lesion size (17.3 ± 23.8 vs. 2.0 ± 1.5 cm2; p < 0.001) was greater with CNEO vs. CTHR, as was systemic disease burden (cancer-involved organs: 3.6 ± 2.0 vs. 2.3 ± 2.1; p = 0.02). Mortality during a median follow-up of 2.5 years was markedly higher among patients with CNEO compared to those with CTHR (HR = 3.13 [CI 1.54-6.39], p = 0.002); prognosis was similar when patients were stratified by lesion size assessed via area (HR = 0.99 per cm2 [CI 0.98-1.01], p = 0.40) or maximal diameter (HR = 0.98 per cm [CI 0.91-1.06], p = 0.61). CTHR conferred similar mortality risk compared to cancer-matched controls without cardiac involvement (p = 0.64) whereas mortality associated with CNEO was slightly higher albeit non-significant (p = 0.12). CONCLUSIONS: Among a broad cancer cohort with cardiac masses, CNEO defined by LGE-CMR tissue characterization conferred markedly poorer prognosis than CTHR, whereas anatomic assessment via cine-CMR did not stratify mortality risk. Both CNEO and CTHR are associated with similar prognosis compared to CMASS - controls matched for cancer type and disease extent.

How to Develop a Cardio-oncology Fellowship.

Management of cardiovascular disease in patients with cancer and cancer survivors requires particular clinical expertise and skills that are central to cardio-oncology. The areas of knowledge required include specific cardiovascular complications directly related to oncologic therapies and the impact of cancer and its therapies on existing or potential cardiovascular comorbidities. Many cancer therapeutics have potential cardiotoxicity. The conversion of many cancers to chronic conditions, rather than fatal diseases, has produced a population of patients with cancer at high risk for cardiovascular diseases that require specialized knowledge of treating physicians. Thus, there is a compelling need for enhanced cardio-oncology training.

Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Patients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points. RESULTS: Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline. CONCLUSION: The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer. IMPLICATIONS FOR PRACTICE: Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

Risk of Vascular Toxicity with Platinum Based Chemotherapy in Elderly Patients with Bladder Cancer.

PURPOSE: Platinum based chemotherapy is widely used for bladder cancer but is associated with vascular toxicity, especially thromboembolism. We evaluated the short-term (less than 1 year) and intermediate-term (2 to 5 years) vascular toxicity of platinum agents in older patients with bladder cancer. MATERIALS AND METHODS: We identified Medicare beneficiaries 66 to 94 years old diagnosed with stage II-III bladder cancer from 1998 to 2007 in the SEER-Medicare database. We measured the association between platinum based chemotherapy and vascular events (thromboembolic and nonthromboembolic) using Cox proportional hazard regression models. RESULTS: The sample included 5,057 patients, of whom 21.3% received platinum based chemotherapy. Patients receiving platinum based chemotherapy were more likely to be younger and male with less comorbidity than those not receiving any chemotherapy. During the first year after diagnosis the patients who received platinum based chemotherapy had a higher risk of a thromboembolic event (19.8% vs 11.6%, AHR 1.43, 95% CI 1.17-1.75) compared to those who did not receive chemotherapy. The likelihood of having a thromboembolic outcome was similar whether platinum chemotherapy was cisplatin based (21.1%, AHR 1.56, 95% CI 1.22-2.00) or carboplatin based (18.9%, AHR 1.35, 95% CI 1.07-1.71). During years 2 to 5 after diagnosis there was no significant association between platinum chemotherapy and the risk of thromboembolic events. The risk of nonthromboembolic vascular events was not increased with platinum chemotherapy in either period. CONCLUSIONS: Patients receiving platinum based chemotherapy were at higher risk for thromboembolism but not other vascular events, particularly in the first year after diagnosis. This risk of thromboembolism is similar for cisplatin and carboplatin.

Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction.

BACKGROUND: Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatment-induced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment. We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF. METHODS: We retrospectively evaluated patients with HER2-positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of ≥10% to below 55% or an absolute decrease of ≥16%. Logistic regression was used to determine the association between candidate risk factors and treatment-induced cardiotoxicity. RESULTS: Among 573 patients, 92 (16%) developed treatment-induced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity­all were asymptomatic with LVEF of ≥50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%-63%), and none developed heart failure during follow-up. Risk factors associated with treatment-induced cardiotoxicity included age (p = .011), anthracycline chemotherapy (p = .002), and lower pretrastuzumab LVEF (p < .001). CONCLUSION: Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of ≥50%, continuous trastuzumab therapy appears to be safe.

Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer.

Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p < 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p < 0.0001) and trastuzumab (62 vs. 67 %, p < 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.

Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival.

To evaluate how often trastuzumab therapy is ended early (i.e., early discontinuation) and how cardiovascular events and early discontinuation affect survival among older women with breast cancer. A population-based cohort of female Medicare beneficiaries with stage I-III breast cancer in 2005-2009 who received trastuzumab was assembled and followed through 2011. Completed trastuzumab treatment was defined as ≥11 months of continuous trastuzumab treatments with no delay between trastuzumab treatments >45 days. We identified trastuzumab-associated cardiovascular events as those occurring within 45 days before or after the last trastuzumab treatment. Using Cox proportional hazard models, we examined the association between early discontinuation of trastuzumab and cardiovascular events on all-cause mortality. Our cohort consisted of 585 women (mean age: 71.6 years). Approximately 41 % of women discontinued trastuzumab therapy early. Patients with early discontinuation of trastuzumab were more likely to have heart failure /cardiomyopathy, atrial fibrillation, and other cardiovascular events than women who completed trastuzumab. Cardiovascular events were strongly associated with an increased risk of all-cause mortality [adjusted hazard ratio (AHR) 3.54; 95 % confidence interval (CI) 1.87 to 6.68]. Women with early discontinuation of trastuzumab had a non-significant increase in risk of all-cause mortality (AHR: 1.74; 95 % CI 0.94 to 3.23), compared to women who completed trastuzumab. Early trastuzumab discontinuation was common among older patients, and often associated with adverse cardiovascular events. Development of cardiovascular events was associated with a higher mortality risk than early trastuzumab discontinuation, implying that reducing cardiovascular complications from trastuzumab therapy could likely have a substantive impact on overall survival in this population.

Cardiomyopathy associated with cancer therapy.

Chemotherapy-associated cardiomyopathy is a well known cardiotoxicity of contemporary cancer treatment and a cause of increasing concern for both cardiologists and oncologists. As cancer outcomes improve, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Asymptomatic or symptomatic left ventricular systolic dysfunction in the setting of cardiotoxic chemotherapy is an important entity to recognize. Early diagnosis of cardiac injury through the use of novel blood-based biomarkers or noninvasive imaging modalities may allow for the initiation of cardioprotective medications or modification of chemotherapy regimen to minimize or prevent further damage. Several clinical trials are currently underway to determine the efficacy of cardioprotective medications for the prevention of chemotherapy-associated cardiomyopathy. Implementing a strategy that includes both early detection and prevention of cardiotoxicity will likely have a significant impact on the overall prognosis of cancer survivors. Continued coordination of care between cardiologists and oncologists remains critical to maximizing the oncologic benefit of cancer therapy while minimizing any early or late cardiovascular effects.

Cardiac metastases from head and neck cancer mimicking a myocardial infarction.

Cardiac metastases from head and neck cancer are rare. We present 2 patients with primary head and neck cancer found to have cardiac metastases. Electrocardiograms showed a persistent acute infarction pattern due to myocardial tumor infiltration. No cardiac symptoms were present. Both patients died of metastatic disease.